Emerging physiologic and genetic data suggest that dysfunction of the pancreatic beta cell is the key determinant of whether an insulin resistant individual will progress to frank hyperglycemia and diabetes. The long-range goal of this applicant is to define the pathways that govern beta cell function and survival in states of health in order to understand how these regulatory circuits are impaired in the pathologic state of Type 2 diabetes mellitus. The sarco-endoplasmic reticulum calcium ATPase or SERCA pump resides in the endoplasmic reticulum membrane and is responsible for maintaining a steep calcium concentration gradient between the cytosol and endoplasmic reticulum. In the beta cell, this gradient plays a key role in regulated insulin secretion and the maintenance of endoplasmic reticulum health and function. Preliminary and published work has revealed that expression of the predominant beta cell isoform, SERCA2, is markedly downregulated in rodent and human models of Type 2 diabetes mellitus. Furthermore, loss of SERCA2 expression leads to profound changes in beta cell secretory function and intracellular calcium flux in response to glucose. Given this background, the overall hypothesis of this proposal is that dysregulation of SERCA2 activity and expression is a key contributor to the beta cell dysfunction and death observed in Type 2 diabetes mellitus. To test this hypothesis, three aims are proposed.
Aim 1 : elucidate the in vivo role of SERCA2 in beta cell function using two novel mouse models of SERCA2 deficiency.
Aim 2 : delineate the transcriptional pathways that regulate SERCA2 expression in the pancreatic beta cell under normal conditions and in diabetes.
Aim 3 : elucidate the contribution of microRNAs in disruption of the SERCA2 gene regulatory network. The successful completion of these aims will precisely define the role of islet beta cell SERCA2 in metabolic and glucose homeostasis and identify the pathways that lead to its transcriptional dysregulation in Type 2 diabetes mellitus.

Public Health Relevance

Type 2 diabetes mellitus affects nearly 1 in 12 Americans and is a leading cause of blindness, kidney failure, amputations, and heart disease. Dysfunction of the insulin producing beta cells in the pancreas plays a prominent role in the development of diabetes. The goal of this project is to define the molecular pathways that lead to beta cell failure in Type 2 diabetes in order to inform the development of novel and improved therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK093954-02
Application #
8333338
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Appel, Michael C
Project Start
2011-09-15
Project End
2016-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$334,950
Indirect Cost
$117,450
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Ocaña, Gail J; Pérez, Liliana; Guindon, Lynette et al. (2017) Inflammatory stress of pancreatic beta cells drives release of extracellular heat-shock protein 90?. Immunology 151:198-210
Sims, Emily K; Lakhter, Alexander J; Anderson-Baucum, Emily et al. (2017) MicroRNA 21 targets BCL2 mRNA to increase apoptosis in rat and human beta cells. Diabetologia 60:1057-1065
Maddatu, Judith; Anderson-Baucum, Emily; Evans-Molina, Carmella (2017) Smoking and the risk of type 2 diabetes. Transl Res 184:101-107
Hatanaka, Masayuki; Anderson-Baucum, Emily; Lakhter, Alexander et al. (2017) Chronic high fat feeding restricts islet mRNA translation initiation independently of ER stress via DNA damage and p53 activation. Sci Rep 7:3758
Ferrara, Christine Therese; Geyer, Susan Michelle; Liu, Yuk-Fun et al. (2017) Excess BMI in Childhood: A Modifiable Risk Factor for Type 1 Diabetes Development? Diabetes Care 40:698-701
Bone, Robert N; Evans-Molina, Carmella (2017) Combination Immunotherapy for Type 1 Diabetes. Curr Diab Rep 17:50
Meah, Farah A; DiMeglio, Linda A; Greenbaum, Carla J et al. (2016) The relationship between BMI and insulin resistance and progression from single to multiple autoantibody positivity and type 1 diabetes among TrialNet Pathway to Prevention participants. Diabetologia 59:1186-95
Watkins, Renecia A; Evans-Molina, Carmella; Terrell, Jennifer K et al. (2016) Proinsulin and heat shock protein 90 as biomarkers of beta-cell stress in the early period after onset of type 1 diabetes. Transl Res 168:96-106.e1
Sims, Emily K; Chaudhry, Zunaira; Watkins, Renecia et al. (2016) Elevations in the Fasting Serum Proinsulin-to-C-Peptide Ratio Precede the Onset of Type 1 Diabetes. Diabetes Care 39:1519-26
Saeed, Zeb; Taleb, Solaema; Evans-Molina, Carmella (2016) A case of extragastrointestinal stromal tumor complicated by severe hypoglycemia: a unique presentation of a rare tumor. BMC Cancer 16:930

Showing the most recent 10 out of 41 publications